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Titolo:
A four amino acid deletion polymorphism in the third intracellular loop ofthe human alpha(2C)-adrenergic receptor confers impaired coupling to multiple effectors
Autore:
Small, KM; Forbes, SL; Rahman, FF; Bridges, KM; Liggett, SB;
Indirizzi:
Univ Cincinnati, Coll Med, Dept Med, Cincinnati, OH 45267 USA Univ Cincinnati Cincinnati OH USA 45267 ept Med, Cincinnati, OH 45267 USA Univ Cincinnati, Coll Med, Dept Mol Genet, Cincinnati, OH 45267 USA Univ Cincinnati Cincinnati OH USA 45267 l Genet, Cincinnati, OH 45267 USA
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 30, volume: 275, anno: 2000,
pagine: 23059 - 23064
SICI:
0021-9258(20000728)275:30<23059:AFAADP>2.0.ZU;2-Z
Fonte:
ISI
Lingua:
ENG
Soggetto:
ACOUSTIC STARTLE REFLEX; HUMAN BETA(2)-ADRENERGIC RECEPTOR; ALPHA-2-ADRENERGIC RECEPTORS; ALPHA(2)-ADRENERGIC RECEPTOR; GENETIC ALTERATION; PHOSPHOLIPASE-C; DOWN-REGULATION; SUBTYPE; AGONIST; EXPRESSION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
38
Recensione:
Indirizzi per estratti:
Indirizzo: Liggett, SB Univ Cincinnati, Coll Med, Dept Med, 231 Bethesda Ave,Rm 7507,Cincinnati,OH 45267 USA Univ Cincinnati 231 Bethesda Ave,Rm 7507 Cincinnati OH USA 45267
Citazione:
K.M. Small et al., "A four amino acid deletion polymorphism in the third intracellular loop ofthe human alpha(2C)-adrenergic receptor confers impaired coupling to multiple effectors", J BIOL CHEM, 275(30), 2000, pp. 23059-23064

Abstract

The alpha(2)-adrenergic receptors (alpha(2)ARs) play a critical role in modulating neurotransmitter release in the central and peripheral sympatheticnervous systems. A polymorphism of the alpha(2C)AR subtype localized to human chromosome 4 (the pharmacologic alpha(2C)AR subtype) within an intracellular domain has been identified in normal individuals. The polymorphism (denoted De1322-325) is because of an in-frame 12-nucleic acid deletion encoding a receptor lacking Gly-Ala-Gly-Pro in the third intracellular loop. To delineate the functional consequences of this structural alteration, Chinese hamster ovary cells were permanently transfected with constructs encodingwild-type human alpha(2C)AR and the polymorphic receptor, The De1322-325 variant had decreased high affinity,agonist binding (K-H = 7.3 +/- 0.95 vel sus 3.7 +/- 0.43 nM; %R-H = 31 +/- 4 versus 49 +/- 4) compared with wild-type indicating impaired formation of the agonist-receptor-C: protein complex, The polymorphic receptor displayed markedly depressed epinephrine-promoted coupling to G(i), inhibiting adenylyl cyclase by 10 +/- 4.3% compared with 73 +/- 2.4% for wild-type alpha(2C)AR, This also was so for the endogenous ligand norepinephrine and full and partial synthetic agonists, Depressed agonist-promoted coupling to the stimulation of MAP kinase (similar to 71% impaired) and inositol phosphate production (similar to 60% impaired) was also found with the polymorphic receptor. The Del322-325 receptor was similar to 10 times more frequent in African-Americans compared with Caucasians (allele frequencies 0.381 versus 0.040). Given this significant loss of function phenotype in several signal transduction cascades and the skewed ethnic prevalence, Del322-325 represents a pharmacoethnogenetic locus and may also be the basis for interindividual variation in cardiovascular or central nervous system pathophysiology.

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Documento generato il 19/01/20 alle ore 06:11:36